Antiglutamatergic Therapy to Protect the Brain Against Nerve Agents

抗谷氨酸治疗可保护大脑免受神经毒剂的侵害

基本信息

批准号：
10685433
负责人：
Maria F. Braga
金额：
$ 74.93万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685433
关键词：
Acetylcholinesterase Acute Adult Advanced Development Amygdaloid structure Anticonvulsants Anxiety Appearance Applications Grants Atrophic Behavioral Benzodiazepines Brain Brain Injuries Brain Pathology Caring Cessation of life Chemical Weapons Clinical Combined Modality Therapy Communication Data Deterioration Development Diazepam Drug Kinetics Effectiveness Elderly Electroencephalography Epileptogenesis Exposure to FDA approved Female Funding Glutamates Goals Grant Hippocampus Interneurons Joints Lead Legal patent Licensure Longevity Longitudinal Studies Magnetic Resonance Imaging Measures Medical Midazolam Military Personnel Morbidity - disease rate Muscarinics N-Methyl-D-Aspartate Receptors NMDA receptor antagonist National Institute of Allergy and Infectious Disease Nature Nerve Degeneration Neurologic Organophosphorus Compounds Peripheral Population Property Rattus Recurrence Research Risk Seizures Soman Status Epilepticus Survival Rate Synaptic Transmission Technology Transfer Terrorism Testing Time Toxic effect War Work aged antagonist anxiety-like behavior chemical threat cholinergic cost efficacious treatment efficacy evaluation excitotoxicity male medical countermeasure nerve agent neuron loss neuropathology neuroprotection postnatal pre-clinical pre-clinical research prevent receptor receptor internalization young adult

项目摘要

Nerve agents are lethal chemical weapons that have been used in war and terrorist attacks, with devastating consequences. The risk for mass exposure to nerve agents is presently very high. One of the clinical manifestations of acute exposure to nerve agents is seizure activity progressing to status epilepticus (SE), which can lead to death, or brain damage. It is imperative that medical countermeasures against the toxic effects of nerve agents are developed and become available, which will not only save lives, but also protect against brain damage caused by prolonged SE, and the ensuing long-term morbidities. Currently, diazepam (DZP) is the FDA-approved anticonvulsant for the treatment of nerve agent-induced SE, and its replacement by midazolam (MDZ) is under consideration. There is ample evidence, however, indicating that neither benzodiazepine has satisfactory antiseizure and neuroprotective efficacy. Therefore, a more efficacious therapy is needed to replace DZP and MDZ. We have already completed a significant amount of research in soman-exposed rats, demonstrating that an AMPA/GluK1 receptor antagonist, LY293558 (tezampanel), exerts a far superior antiseizure and neuroprotective efficacy in comparison with DZP or MDZ. However, we also found that 6 months after exposure (a long time for the life span of a rat), even LY293558-treated rats presented evidence of brain damage, suggesting a progressive nature of the induced neuropathology, and indicating the importance of long-term studies in evaluating the neuroprotective efficacy of an anticonvulsant. Therefore, to enhance neuroprotective efficacy, we subsequently tested the combination of LY293558 with an NMDA receptor antagonist—we used caramiphen, an antimuscarinic with NMDA receptor antagonistic properties—and found complete protection against brain damage up to 6 months after soman exposure. Most of these studies have been conducted in young rats (postnatal day 21 or 12). The goal of the present application is to test LY293558+caramiphen in adult male and female rats, in order to complete all the preclinical research necessary to lead this highly efficacious combination therapy to the stage of advanced development. We will include aged rats in the proposed studies, in order to obtain preclinical data pertinent to the elderly population, which is more difficult to protect. Comparisons will be made with soman-exposed rats treated with MDZ. The anticonvulsants will be administered at 1 h after soman exposure in order to simulate a real case scenario of mass exposure, when medical care is unlikely to available immediately. Our central hypothesis is that LY293558+caramiphen will prove to be far superior to MDZ in controlling soman-induced seizures, preventing neuronal degeneration, neuronal loss, GABAergic interneuronal loss, atrophy and pathophysiological alterations in the amygdala and hippocampus, overall brain pathology as revealed by MRI, as well as neurological (development of spontaneous recurrent seizures – epileptogenesis) and behavioral (increased anxiety-like behavior) abnormalities, studied up to 6 months postexposure.

神经毒剂是致命的化学武器，曾用于战争和恐怖袭击，具有毁灭性目前，大规模接触神经毒剂的风险非常高。急性接触神经毒剂的表现是癫痫发作进展为癫痫持续状态（SE），这可能导致死亡或脑损伤，因此必须采取针对有毒物质的医疗对策。神经毒剂的作用被开发出来并可用，这不仅可以拯救生命，而且可以保护目前，地西泮可预防长期 SE 引起的脑损伤以及随之而来的长期发病率。 (DZP) 是 FDA 批准的用于治疗神经毒剂引起的 SE 的抗惊厥药，及其替代品然而，有充分的证据表明，咪达唑仑 (MDZ) 两者都不是。苯二氮卓类药物具有令人满意的抗惊厥和神经保护功效，因此更为有效。需要治疗来替代 DZP 和 MDZ 我们已经完成了大量的研究。暴露于梭曼的大鼠，证明 AMPA/GluK1 受体拮抗剂 LY293558（tezampanel）发挥作用与 DZP 或 MDZ 相比，其抗癫痫和神经保护功效要好得多。发现暴露后 6 个月（对于大鼠的寿命来说很长一段时间），即使是接受 LY293558 治疗的大鼠提出了脑损伤的证据，表明诱导的神经病理学具有渐进性，并且表明长期研究在评估抗惊厥药的神经保护功效方面的重要性。因此，为了增强神经保护功效，我们随后测试了 LY293558 与 NMDA 受体拮抗剂——我们使用卡米芬，一种具有 NMDA 受体拮抗作用的抗毒蕈碱药特性——并发现在接触梭曼后 6 个月内可以完全防止脑损伤。这些研究的目标是在幼鼠（出生后 21 或 12 天）中进行。应用是在成年雄性和雌性大鼠中测试LY293558+caramiphen，以完成所有为使这种高效的联合疗法进入高级阶段，需要进行临床前研究我们将在拟议的研究中纳入老年大鼠，以获得与此相关的临床前数据。老年人群，其保护难度更大，将与梭曼暴露大鼠进行比较。暴露于索曼后 1 小时将使用 MDZ 治疗，以模拟大规模暴露的真实案例，而我们的中心不太可能立即提供医疗服务。假设 LY293558+caramiphen 在控制梭曼诱导方面远优于 MDZ 癫痫发作，预防神经元变性、神经元丢失、GABA能神经元间丢失、萎缩和杏仁核和海马体的病理生理学改变，MRI 显示的整体大脑病理学，以及神经学（自发性反复发作的发展 - 癫痫发生）和行为学（焦虑样行为增加）异常，在暴露后 6 个月内进行研究。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preventing Long-Term Brain Damage by Nerve Agent-Induced Status Epilepticus in Rat Models Applicable to Infants: Significant Neuroprotection by Tezampanel Combined with Caramiphen but Not by Midazolam Treatment.

在适用于婴儿的大鼠模型中预防神经毒剂诱发的癫痫持续状态的长期脑损伤：替赞帕奈联合卡米芬具有显着的神经保护作用，但咪达唑仑治疗则没有显着的神经保护作用。

DOI：
发表时间：
2024-01-17
期刊：
影响因子：
0
作者：
De Araujo Furtado, Marcio;Aroniadou;Figueiredo, Taiza H;Pidoplichko, Volodymyr I;Apland, James P;Rossetti, Katia;Braga, Maria F M
通讯作者：
Braga, Maria F M

Alpha-linolenic acid enhances the facilitation of GABAergic neurotransmission in the BLA and CA1.

α-亚麻酸增强 BLA 和 CA1 中 GABA 能神经传递的促进。

DOI：
发表时间：
2023-04
期刊：
影响因子：
0
作者：
Pidoplichko, Volodymir I;Figueiredo, Taiza H;Braga, Maria Fm;Pan, Hongna;Marini, Ann M
通讯作者：
Marini, Ann M

Mechanisms of Organophosphate Toxicity and the Role of Acetylcholinesterase Inhibition.

有机磷毒性机制和乙酰胆碱酯酶抑制作用。

DOI：
发表时间：
2023-10-18
期刊：
影响因子：
4.6
作者：
Aroniadou;Figueiredo, Taiza H;de Araujo Furtado, Marcio;Pidoplichko, Volodymyr I;Braga, Maria F M
通讯作者：
Braga, Maria F M

Acute and long-term consequences of exposure to organophosphate nerve agents in humans.

人类接触有机磷神经毒剂的急性和长期后果。